Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/NgR-independent pathways that converge at RhoA

Schweigreiter, Rüdiger; Walmsley, Adrian R.; Niederöst, Barbara; Zimmermann, Dieter R.; Oertle, Thomas; Casademunt, Elisabeth; Frentzel, Stefan; Dechant, Georg; Mir, Anis K.; Bandtlow, Christine E.

doi:10.1016/j.mcn.2004.06.004

Cited by 84 publications

(64 citation statements)

References 69 publications

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“…Microtubules are regulated by external signals during axon elongation and guidance (Suter et al, 1998;Buck and Zheng, 2002;Dent and Gertler, 2003). In fact, the known inhibitory cues present in the CNS myelin and the glial scar, including myelinassociated glycoprotein (MAG), Nogo, OMgP (oligodendrocytemyelin glycoprotein), and versican, converge downstream of their receptors onto signaling pathways of the Rho GTPases (Dubreuil et al, 2003;Fournier et al, 2003;Schweigreiter et al, 2004;Sivasankaran et al, 2004), which, in addition to the actin cytoskeleton, also affect microtubule stability and dynamics (Etienne-Manneville, 2004;Mimura et al, 2006). This suggests that extracellular inhibitory molecules could also induce changes in the dynamics and morphology of the axonal tip by affecting microtubule organization.…”

Section: Putative Signaling Mechanisms Underlying Microtubule Disorgamentioning

confidence: 99%

Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration

Ertürk¹,

Hellal²,

Enes³

et al. 2007

J. Neurosci.

357

338

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Axons in the CNS do not regrow after injury, whereas lesioned axons in the peripheral nervous system (PNS) regenerate. Lesioned CNS axons form characteristic swellings at their tips known as retraction bulbs, which are the nongrowing counterparts of growth cones. Although much progress has been made in identifying intracellular and molecular mechanisms that regulate growth cone locomotion and axonal elongation, a comprehensive understanding of how retraction bulbs form and why they are unable to grow is still elusive. Here we report the analysis of the morphological and intracellular responses of injured axons in the CNS compared with those in the PNS. We show that retraction bulbs of injured CNS axons increase in size over time, whereas growth cones of injured PNS axons remain constant. Retraction bulbs contain a disorganized microtubule network, whereas growth cones possess the typical bundling of microtubules. Using in vivo imaging, we find that pharmacological disruption of microtubules in growth cones transforms them into retraction bulb-like structures whose growth is inhibited. Correspondingly, microtubule destabilization of sensory neurons in cell culture induces retraction bulb formation. Conversely, microtubule stabilization prevents the formation of retraction bulbs and decreases axonal degeneration in vivo. Finally, microtubule stabilization enhances the growth capacity of CNS neurons cultured on myelin. Thus, the stability and organization of microtubules define the fate of lesioned axonal stumps to become either advancing growth cones or nongrowing retraction bulbs. Our data pinpoint microtubules as a key regulatory target for axonal regeneration.

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Section: Putative Signaling Mechanisms Underlying Microtubule Disorgamentioning

confidence: 99%

Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration

Ertürk¹,

Hellal²,

Enes³

et al. 2007

J. Neurosci.

357

338

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“…Three types of molecules derived from myelin which can suppress axon growth have been identified thus far: Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (Omgp) (1). Previous studies indicate that Nogo-A, MAG and Omgp may activate Rho by common or different pathways and subsequently cause growth cone collapse (33,34).…”

Section: Discussionmentioning

confidence: 99%

The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate

Huang

Wang

Shen

et al. 2012

Molecular Medicine Reports

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Abstract. The aim of this study was to investigate the effects of erythropoietin (EPO) on RhoA/Rho-associated kinase (ROCK) expression in rat retinal explants cultured with glutamate. After the retinal explants were cultured in serumfree R16 nutrient medium for 24 h, the retinal explants were divided into control (R16 nutrient medium), glutamate (R16 nutrient medium containing 5 mM/l glutamate) and glutamate + EPO (R16 nutrient medium containing 5 mM/l glutamate and 6.0 U/ml EPO) groups, and culturing was continued for another 72 h. The mRNA and protein expression of total RhoA, ROCK1 and ROCK2 in the retinal explants was examined by RT-PCR and western blotting, and active RhoA in the retinal explants was detected via GST-RBD binding and immunoblotting with an antibody specific to active RhoA. The total RhoA mRNA and protein expression did not differ substantially between the control, the glutamate and the glutamate + EPO groups. The glutamate increased the active RhoA, ROCK1 and ROCK2 expression in cultured retinal explants (P<0.05), whereas the expression of active RhoA, ROCK1 and ROCK2 in the glutamate + EPO group was significantly lower than that in the simple glutamate group (P<0.05) and similar to that in the control group. In conclusion, EPO downregulates active RhoA, ROCK1 and ROCK2 expression in retinal explants cultured with glutamate.

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“…Subsequent studies documented its presence in the developing and adult CNS (Milev et al, 1998;Schmalfeldt et al, 1998;Popp et al, 2003Popp et al, , 2004Schweigreiter et al, 2004). In general, versican is believed to be synthesized primarily by glial cells Niederöst et al, 1999;Asher et al, 2002) and to be expressed at higher levels in postnatal than in embryonic brain (Bignami et al, 1993;Milev et al, 1998).…”

Section: Versican As a Laminar Markermentioning

confidence: 99%

“…(2) Versican bears multiple active sites that interact with a variety of receptors, including annexin 6, CD44, and integrins (Kawashima et al, 2000;Takagi et al, 2002;Wu et al, 2002), all of which are expressed in the nervous system. Such interactions activate signal transduction pathways (Zhang et al, 1998;Schweigreiter et al, 2004) that could lead to presynaptic differentiation. (3) Versican interacts not only with cells but also with other components of the ECM, including tenascin-R, link proteins, fibulin, and hyaluronan Aspberg et al, 1997;Olin et al, 2001;Matsumoto et al, 2003).…”

Section: Versican As a Vva Ligandmentioning

confidence: 99%

“…Lecticans are present in the embryonic as well as the postnatal brain (Margolis and Margolis, 1993;Bandtlow and Zimmermann, 2000;Silver and Miller, 2004), and they exert a striking inhibitory effect on neurite outgrowth in vitro (Schmalfeldt et al, 2000;Schweigreiter et al, 2004). In contrast to growing knowledge about roles of lecticans in the postnatal brain, however, little is known about their roles in embryonic neural development.…”

Section: Introductionmentioning

confidence: 99%

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Versican in the Developing Brain: Lamina-Specific Expression in Interneuronal Subsets and Role in Presynaptic Maturation

Yamagata¹,

Sanes²

2005

J. Neurosci.

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Chondroitin sulfate proteoglycans (CSPGs) of the extracellular matrix help stabilize synaptic connections in the postnatal brain and impede regeneration after injury. Here, we show that a CSPG of the lectican family, versican, also promotes presynaptic maturation in the developing brain. In the embryonic chick optic tectum, versican is expressed selectively by subsets of interneurons confined to the retinorecipient laminae, in which retinal axons arborize and form synapses. It is a major receptor for the Vicia villosa B 4 lectin (VVA), shown previously to inhibit invasion of the retinorecipient lamina by retinal axons (Inoue and Sanes, 1997). In vitro, versican promotes enlargement of presynaptic varicosities in retinal axons. Depletion of versican in ovo, by RNA interference, results in retinal arbors with smaller than normal varicosities. We propose that versican provides a lamina-specific cue for presynaptic maturation and discuss the related but distinct effects of versican depletion and VVA blockade.

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Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/NgR-independent pathways that converge at RhoA

Cited by 84 publications

References 69 publications

Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration

Disorganized Microtubules Underlie the Formation of Retraction Bulbs and the Failure of Axonal Regeneration

The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate

Versican in the Developing Brain: Lamina-Specific Expression in Interneuronal Subsets and Role in Presynaptic Maturation

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